Project team (from the left):

Barbro Burt, Technician
Tiina Skoog, PhD Student
Carl Whatling,Visiting Senior Researcher
Per Eriksson, Senior Researcher
Hanna Björck, PhD Student
Sofia Pettersson, PhD Student

Recent publications:

Jormsjö S, Whatling C, Walter DH, Zeiher AM, Hamsten A and Eriksson P. 
Allele-specific regulation of matrix metalloproteinase-7 promoter activity is associated with coronary artery luminal dimensions amongst hypercholesterolemic patients.
Arterioscler Thromb Vasc Biol 2001;21:1834-1839.

Banfi C, Eriksson P, Mussoni L, Sironi L, Hamsten A and Tremoli E. 
Transcriptional regulation of plasminogen activator inhibitor type 1 gene by insulin: Insights into the signaling pathway.
Diabetes 2001;50:1522-1530.

Jormsjö S, Ye S, Moritz J, Walter DH, Dimmeler S, Zeiher AM, Henney A, Hamsten A and Eriksson P. 
Differential regulation of matrix metalloelastase gene activity influeces coronary artery luminal dimensions in diabetic patients with manifest coronary artery disease.
Circ Res 2000;86:998-1003.

Matrix-degrading proteases as candidate genes for vascular disease

The overall goal of the project is to study the expression and function of matrix-degrading proteases and their inhibitors in vascular disease such as atherosclerosis, plaque rupture and aortic aneurysm formation. Our approach is to use expression studies  to identify disease-related proteases. A combination of human genetic studies in well-characterised clinical cohorts and in vitro experiments are used subsequently to characterise the functional and clinical relevances of these proteases.

Impaired proteolytic activity has been implicated in atherogenesis and the precipitation of acute coronary syndromes by regulating connective tissue remodelling, thus determining the volume expansion of the atherosclerotic plaque, its stability and the potential for smooth muscle cell proliferation. Several groups of proteases have been suggested to be involved in the remodelling of the extracellular matrix (ECM). Members of the serine proteases, such as plasmin, tissue-type and urokinase-type plasminogen activators, are able to degrade parts of the ECM. Cysteine and aspartic proteases such as the cathepsins have the capacity to degrade elastin fibres. However, the most important family of matrix-degrading enzymes is probably the matrix metalloproteinases (MMPs) since these proteases can degrade all macromolecules present in the connective tissue matrix. Finally, the catalytic activity of the different families of proteases is regulated by groups of specific inhibitors e.g. tissue-inhibitors of metalloproteinases (TIMP), plasminogen activator inhibitors (PAI) and cystatins, all of which inactivate the proteolytic activity by forming an inactivation complex.

The specific aims of the project are: 1. Identify and characterize genes involved in degradation of ECM using gene expression arrays - an emphasis on proteases involved in vascular disease. 2. Identify and characterise metabolically and cytokine regulated proteolytic enzymes within the atherosclerotic plaque 3. Discover common genetic variation within members of the MMP and cathepsin family of proteolytic enzymes and their inhibitors expressed in human vascular tissue and characterise the clinical significance of variants identified in relation to vascular disease such as atherosclerosis, plaque rupture and aneurysm.


Tumour necrosis factor-a: genetic regulation and implications for coronary artery disease

The objective of this project is to study how the expression of tumour necrosis factor-a (TNF-a) is regulated genetically and to investigate the role of TNF-a in coronary artery disease.

Disturbances of TNF-α metabolism have been implicated in several disorders, such as obesity and insulin resistance, indicating that perturbations of TNF-α metabolism may affect the onset of non-insulin-dependent diabetes mellitus and play a role in the development of cardiovascular disorders. Indeed, increased plasma concentrations of TNF-α have been found in patients with premature coronary artery disease.

Specific aims of the study are to screen the proximal promoter of the TNF-α gene for polymorphism(s) that may affect the expression of the gene, to characterise the possible functional polymorphic sites in the promoter of the gene at a molecular level and to study the role of TNF-α and the effect of its promoter polymorphisms in different diseases, particularly in atherosclerosis.